We propose to study peripheral mechanisms that underlie behavioral hyperalgesia and primary afferent sensitization to mechanical stimuli, including mechanisms involving direct action on the primary afferent, as well as mechanisms involving indirect action on the sympathetic postganglionic neuron. We will also evaluate mechanisms that contribute to hyperalgesia in experimental diabetes. We have provided evidence that primary afferent sensitization involves the cAMP second messenger system. We plan to study further the signal transduction mechanism(s) of primary afferent sensitization including an evaluation of the prostaglandin receptor involved, and the contribution of G-proteins and the cAMP second messenger system, as well as conductance changes, to the decrease in threshold and the enhanced rate of firing in sensitized neurons. The studies use both behavioral experiments and electrophysiological techniques, including isolated single-fiber preparations and whole-cell clamping of acutely dissociated dorsal toot ganglion neurons. Sympathetic postganglionic neuron (SPGN)-dependent hyperalgesia will be studied in terms of specific pathways involved in prostaglandin synthesis, the receptor action of bradykinin, and interactions between norepinephrine and prostaglandin synthesis. Behavioral and biochemical studies will be used. The modulatory action of opioids on SPGN-dependent hyperalgesia, as well as on primary afferent sensitization will also be investigated. These sensitization mechanisms are often seen with tissue injury and inflammation. To evaluate the contribution of these mechanisms to sensitization, in the absence of inflammation, such as after nerve injury, we will also study the streptozotocin-treated diabetic rat. We will study effects of cAMP metabolism, protein kinase A and protein kinase C on diabetic hyperalgesia. Possible pathophysiological responses of the diabetic nociceptor will be investigated. In summary, we propose a series of interdisciplinary experiments that will provide new information about the peripheral neuronal mechanisms of pain and hyperalgesia in both normal and disease states.
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